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Review of the choice and use of

Stephen Bleakley MRPharmS, MSc, MCMHP As part of our updated series of articles on the major psychiatric groups, produced in association with the College of Mental Health Pharmacy (www.cmhp.org.uk), Stephen Bleakley describes the use of antidepressants through a review of the most recent clinical literature. , interactions and side-effects as well as drug choice and information to give to patients are discussed.

5-HT noradrenaline SNRI (eg ) have two or more episodes despite active treatment. Having longer and more frequent episodes, being sin- gle, having a low income and old age all worsen the prognosis.2,3 nerve terminal Antidepressants are effective and accessible treat- ment options that can reduce suffering and prevent relapse of symptoms. They are recommended as first- line treatment options in moderate and severe or mild or subthreshold depression that has persisted despite other interventions. Anti- depressants are not first-line treatment for short dura- MAO MAO tion mild or subthreshold depression or for 4,5 mitochondria mitochondria depression in children and adolescents. COMT This article gives an overview of the pharmaco- therapy for treating depression.

5-HT re-uptake noradrenaline Evidence base supporting pharmacotherapy transporter re-uptake Antidepressants are undoubtedly effective but spon- transporter taneous remission of symptoms and a significant synaptic COMT effect can complicate trials. cleft Spontaneous improvement from depression can MAO noradrenaline occur in up to 20 per cent of sufferers within four to 5-HT 6 eight weeks. Placebo response appears to have an receptor effect over and above spontaneous improvement with post-synaptic membrane 30 per cent of sufferers achieving a response in short- © CNSForum.com term studies.5 In the same studies, antidepressants 5,7 Figure 1. The mechanism behind and noradrenaline reuptake inhibition. achieve a response rate of around 50 per cent. SNRI: serotonin and noradrenaline ; MAO: monoamine oxidase, COMT: Remission, which should be the aim of treatment, catechol-o-methyltransferase. Reproduced with permission www.cnsforum.com/ occurs in up to 50 per cent of patients prescribed anti- imagebank/item/Drug_SNRI/default.aspx depressants and 25-35 per cent of patients assigned to a placebo.4 This indicates that even after acute epression is a common and recurrent disorder treatment with antidepressants, half of patients will Daccounting for significant morbidity and mortal- continue to have symptoms. As the severity of depres- ity worldwide. Depression affects approximately 8-12 sion increases, the antidepressant to placebo differ- per cent of the global population and is currently the ence increases in favour of antidepressants. There is, leading cause of disability worldwide (in terms of total however, some debate as to when the separation in years lost due to disability).1 Following a first episode effect becomes clinically significant.8,9 One leading of depression, 22 per cent of sufferers will continue to meta-analysis suggested that antidepressants only have symptoms after a year and up to 85 per cent will achieve a clinically significant effect size (Cohen d of

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Drug Main mode Adverse effects Half- Toxicity in Additional information of action Sedation Anti- Nausea/ Sexual life, over-dose cholin- vomiting dysfunction hours ergic

Selective serotonin inhibitors (SSRIs) SRI - - ++ ++ ~30 Moderate Associated with QTc prolongation at high doses. SRI - - ++ ++ ~30 Low Associated with QTc prolongation at high doses. SRI - - ++ ++ 96-144 Low SRI + - ++ ++ 17-22 Low Twice daily dose above 150mg/day. Rarely used in practice SRI + - ++ ++ ~24 Low Discontinuation symptoms common SRI - - ++ ++ ~26 Low

Tricyclic antidepressants (TCAs) SRI+ NRI +++ +++ - + 9-25 High SRI ++ +++ + ++ 12-36 Moderate SRI+ NRI +++ ++ - + 14-40 High Not recommended by (dothiepin) NICE NRI + ++ - + ~5 Low SRI+ NRI ++ +++ - + 4-18 High NRI + ++ - + 18-96 High SRI+ NRI ++ +++ - + 7-23 High

Monoamine oxidase inhibitors (MAOIs) - Specialist use only Irreversible + ++ + + ? High MAOI Irreversible + + + + 1.5 High MAOI Irreversible - + + + 2.5 High MAOI Reversible - - + - ~3 Low MAOI

Other antidepressants M1,2 + - - - - 1-2 Unclear 5-HT2c probably low * NRI+DRI - - - - ~20 Moderate Dose related risk SRI+NRI - - ++ ++ 8-17 Moderate Can increase blood pressure 5-HT2, a1, ++ + - - 12-29 Low Blood dyscrasias reported a2 Rarely used in practice 5-HT2, 5-HT3, +++ - - + 20-40 Low Weight gain is common a2 NRI - + - - ~13 Low 5-HT2, a1, SRI +++ - + + 5-13 Low Venlafaxine SRI+NRI - - ++ +++ 5-15 Moderate Can increase blood pressure

Abbreviations SRI – serotonin reuptake inhibitor; NRI – noradrenaline reuptake inhibitor; DRI – reuptake inhibitor; M1,2 – ; 5-HT2,3 – serotonin receptor specific antagonists; a1,2 – alpha-adrenoreceptor antagonists; +++ = high incidence, ++ = moderate, + = low, - = little or minimum, ? = unknown, * unlicensed in the UK as an antidepressant

Table 1. Adverse reactions and overdose risk of antidepressants16,29

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0.5 or more) at a Hamilton Depression Rating Scale receptors and a 5-HT2c antagonist. The effect on score of 25, ie very severe symptoms.8 A depressive melatonin is thought to improve circadian rhythm episode of longer duration (over one year) is associ- and sleep quality while the 5-HT2c blockade increases ated with a smaller response to placebo while elderly both noradrenaline and dopamine release.14 patients, children and adolescents and those with a severe comorbid medical illness have a poorer Choice of antidepressant response to antidepressants.4 The choice of antidepressant in depression should When effective, statistical separation from placebo always reflect the patient’s preference, past experi- with antidepressants is greatest in the first one to two ences, previous response and any concurrent med- weeks and lowest in weeks 4-6.10 Thus if there is no ical comorbidity or drug therapy. In the absence of response to the antidepressant within the first four special features, the SSRIs are recommended first line weeks of treatment, a change in dose or drug is war- because of their superior safety profile and better tol- ranted. erability compared with TCAs.4,5 The SSRIs are One of the clearest benefits of antidepressant ther- broadly similar in their mechanism of action and apy is in preventing a relapse of depressive symptoms. adverse effect profile (see Table 1) but differ in their The average rate of relapse while on an antidepres- half-life and interaction potential (see Table 2). sant is 18 per cent compared with 41 per cent on Fluoxetine has the longest half-life and is associated placebo over 12 months.11 with a lower risk of discontinuation symptoms while Complex meta-analysis suggests that there may be paroxetine has the shortest half-life and is associated small but important differences in efficacy and toler- with a higher rate of discontinuation symptoms.15 If ability between antidepressants.12 In 2009, Andrea a patient does not respond within three to four weeks Cipriani and colleagues compared 12 newer genera- to the initial SSRI, first check compliance, then the tion antidepressants by re-analysing short-term ran- usual strategy would be to gradually increase the dose. domised controlled trial data in a multiple-treatment It is important to note, however, that there is no evi- meta-analysis. Mirtazapine, sertraline, escitalopram dence supporting a dose-related response in depres- and venlafaxine ranked as the most efficacious anti- sion with any SSRI except escitalopram.4 The TCAs depressants and escitalopram, citalopram, sertraline and the SNRI venlafaxine, however, do have some and bupropion ranked as being better tolerated than indirect evidence supporting a dose-related others.11 This study did not include the older response.4 Should a patient fail to respond or cannot antidepressants (TCAs) or monoamine oxidase tolerate the first SSRI then switching to an alternative inhibitors (MAOIs) and the number of studies SSRI or another antidepressant (such as mirtazapine included for each antidepressant varied considerably. or a TCA) is recommended.4,5 Venlafaxine (although less well tolerated) is a useful option for those who Pharmacology have failed two previous SSRIs.4 All current antidepressants increase the transmission Switching between antidepressants can be prob- of one or more of the monoamines: serotonin, nor - lematic especially when changing from fluoxetine or adrenaline or dopamine. How they achieve this dif- an MAOI to another drug. Readers are fers significantly between antidepressants. The referred to the current edition of a reference book majority – selective serotonin reuptake inhibitors such as the Maudsley Prescribing Guidelines for (SSRIs), TCAs, serotonin and noradrenaline re - advice.16 uptake inhibitors (SNRIs), noradrenaline reuptake inhibitors (NRIs) and noradrenaline and dopamine Treatment-resistant depression reuptake inhibitors (NDRIs) – inhibit the transporter The chance of remission of symptoms reduces signif- responsible for the re-uptake of the monoamines icantly following a failure to respond to the initial anti- (see Figure 1). depressant choices. Augmenting an antidepressant MAOIs block the mitochondrial enzyme with another agent or combining antidepressants is monoamine oxidase, which in turn reduces the break- a useful option but should only be attempted under down of serotonin, noradrenaline and dopamine. advice from a consultant psychiatrist. Augmenting the Mirtazapine is a presynaptic alpha2-adrenoreceptor antidepressant with either (monitoring antagonist that increases noradrenaline and sero- lithium levels closely) or tri-iodothyronine appears a tonin transmission by reducing the action of the useful option (remission rates 15.9 per cent, 24.7 per 13 17 alpha2-adrenoreceptor negative feedback pathway. cent respectively) as does augmentation with an Agomelatine is an agonist at melatonin type 1 and 2 atypical (usually ) or cogni-

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Drug Effect on P450 Levels Levels Increases level of Additional information CYP enzymes increased by decreased by

Citalopram / Substrate at 3A4 Unlikely to cause Escitalopram pharmacokinetic interactions but contraindicated with other drugs which prolong QT interval

Fluoxetine Inhibits 2D6, 2C9, Benzodiazepines 3A4 Carbamazepine As for paroxetine and sertraline

Paroxetine / Inhibits 2D6 Carbamazepine Sertraline Ciclosporin (dose Clozapine dependent) Haloperidol Moclobemide Metoprolol Phenytoin Pimozide TCAs Valproate Warfarin

Tricyclic Substrate 1A2, Diltiazem Carbamazepine antidepressants 2D6, 3A3/4 Duloxetine Fluoxetine Fluvoxamine Haloperidol Paroxetine Phenothiazines Sertraline Terbinafine Verapamil

MAOIs AVOID DIETARY Risk of serotonin syndrome / TYRAMINE (eg dairy, avoid use with other yeast and some serotonin enhancing drugs meat products)

Moclobemide Substrate 2C19, 2D6 Avoid large amounts of dietary tyramine

Agomelatine Substrate mainly 1A2, Fluvoxamine Rifampicin Ciprofloxacin

Duloxetine Minor inhibitor at Ciprofloxacin Warfarin 2D6 Fluvoxamine

Mirtazapine Substrate at 2D6 Fluvoxamine Carbamazepine Not a source or cause of and 1A2 Phenytoin pharmacokinetic interactions

Reboxetine Substrate at 3A4 Carbamazepine Extensively protein bound Avoid with potent 3A4 inhibitors

Trazodone Substrate at 3A4 Clarithromycin Erythromycin

Venlafaxine Substrate at 2D6, 3A4 Haloperidol Avoid with potent 3A4 and 2D6 inhibitors

Table 2. Commonly known pharmacokinetic drug interactions associated with antidepressants16,32,33 (NB. this list is not exhaustive)

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porters. Sertraline, citalopram, escitalopram and ven- lafaxine may have a slightly higher risk than other Diarrhoea Sweating Akathisia Ataxia serotonin reuptake inhibitors (SRIs).20 Combining an SRI with either an NSAID or a systemic corticos- teroid further increases the risk. Concomitant use of an SRI with low-dose aspirin or an antiplatelet drug Mild Life does not appear to increase the incidence beyond that symptoms threatening seen with the SRI alone. In high-risk patients who are prescribed an SRIs, a gastroprotective agent such as lansoprazole or omeprazole is recommended.5,16

Tremor Myoclonus Confusion Convulsions Serotonin syndrome Serotonin syndrome is a potentially life-threatening but preventable adverse reaction that may result from Figure 2. The spectrum of symptoms associated with serotonin syndrome22 the therapeutic use of antidepressants, after an inter- action between two or more serotonin enhancing tive behavioural therapy (CBT).4,5,16 Quetiapine (in drugs or following an overdose of antidepressants. the extended release form) is licensed as an add-on All antidepressants that enhance serotonin have been treatment to antidepressants in those who have not associated with serotonin syndrome as have many responded to antidepressant monotherapy. Although non-antidepressant drugs (for example , the evidence base supporting quetiapine in depres- fentanyl,21 and lithium). Signs and symp- sion is good, it is important to be alert for any adverse toms of serotonin syndrome range from mild diar- effects, eg sedation, hypotension, weight gain or rhoea and tremor to ataxia and convulsions (see emerging diabetes.16 Figure 2). Treatment involves the immediate removal Combining specific antidepressants is another of the offending agent and administration of sup- widely used strategy in treatment-resistant depression. portive therapy. Moderate to severe cases should Mirtazapine with either an SSRI or venlafaxine are receive immediate medical attention. Onset of symp- the most common combinations and are recom- toms is usually rapid, with 60 per cent of patients pre- mended by NICE.5,18 Combining mirtazapine with senting within six hours of the initial precipitating venlafaxine as a fourth-stage treatment option has factor. Any drug that inhibits the metabolism of a been shown to be as effective but better tolerated than serotonergic drug may also worsen or precipitate switching to the MAOI tranylcypromine (remission serotonin syndrome.22 rates were 13.7 per cent for the combined venlafaxine and mirtazapine group versus 6.9 per cent for the Discontinuation symptoms tranylcypromine group).19 However, it is important All antidepressants can cause discontinuation symp- to remember that not all patients will tolerate com- toms, which are usually mild and self-limiting. bining antidepressants and symptoms of serotonin Paroxetine, venlafaxine and MAOIs are associated syndrome must be monitored for. with the most reports.5,23 while fluoxetine and Electroconvulsive therapy (ECT) also remains an agomelatine appear to be less problematic.16 effective and recommended short-term treatment for Symptoms reported when discontinuing SSRIs severe or life-threatening depression.4,5 The benefits include flu-like symptoms, dizziness and electric of ECT, however, are rarely prolonged and an anti- shock sensations.16 These typically peak within the depressant must also be prescribed to reduce the risk first week of withdrawal and taper off after two to of a relapse of symptoms.5 three weeks. Unless there is a severe adverse reac- tion, antidepressants should be discontinued slowly Safety issues over four or more weeks.5 This can be done by reduc- Increased risk of bleeding ing the dose by 20-25 per cent every week but this All antidepressants that inhibit serotonin reuptake depends largely on patient preference. Some may (SSRIs, SNRIs and TCAs) are probably associated with prefer a quicker withdrawal to prevent prolonging an increased risk of bleeding, particularly upper symptoms. Although antidepressants can cause dis- gastrointestinal tract bleeding.20 The mechanism continuation symptoms, they are not associated with behind this is likely to be depletion of serotonin from tolerance, cravings or drug seeking behaviour so are platelets by blocking the serotonin reuptake trans- not considered addictive.

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Drug Company Mode of action Expected Comment UK launch

Vortioxetine / Thought to be a serotonin Q2 2014 Approved by the FDA in (Brintellix) Takeda enhancer with 5HT3 antagonist/ September 2013 5HT1a agonist properties. Other Positive opinion from the serotonin receptors also involved CHMP

Edivoxetine Lilly Selective noradrenaline Q4 2014 Likely to be marketed as an reuptake inhibitor adjunctive treatment in partial responders to SSRIs

Table 3. New antidepressants predicted to launch in 2014

Hyponatraemia • Antidepressants are an effective treatment for those Most antidepressants have been rarely shown to with moderate to severe depression or milder cause hyponatraemia. Any patient showing symp- symptoms that have persisted toms such as dizziness, nausea, confusion, cramps • It is important to inform your doctor and pharmacist and should receive urgent medical atten- of any other prescribed, purchased or herbal tion and have their serum sodium levels checked. before starting an antidepressant Older people, females and those who are under- • As with all medication antidepressants can cause weight are more at risk. Stopping the causative anti- side-effects. Many such as nausea, , depressant immediately, fluid restricting and and drowsiness wear off within a few days. Other considering switching to a different antidepressant side-effects such as sexual dysfunction, weight gain and sweating may persist and should be discussed class is recommended.16 with your doctor or pharmacist • Antidepressant therapy should be continued for at Antidepressants in children and adolescents least six months after the remission of symptoms to Psychological treatments such as CBT or family ther- reduce the risk of a relapse. Longer courses are apy should always be considered first when treating required for those with a more prolonged illness depression in children and adolescents.24 Fluoxetine • Antidepressants are not addictive but should be may be added if the depression is moderate or severe withdrawn slowly as discontinuation symptoms are and unresponsive to alone.16,24 possible. Missing even one dose of some anti - Sertraline may be an option if fluoxetine is not toler- depressants can cause discontinuation symptoms ated or ineffective.16 No other antidepressant is • For patient and carer friendly advice on anti- recommended in children and adolescents. The anti- depressants visit www.choiceandmedication.org depressant should be started at half the usual adult Box 1. Key information for patients dose with weekly monitoring for the first four weeks. Prescribers should observe closely for any signs of sui- orders in under 18 year olds is unfavourable for cidal behaviour, self-harm or hostility during this paroxetine, venlafaxine, sertraline, citalopram, esci- weekly monitoring.24 In young people, antidepres- and mirtazapine sants should be continued for at least six months after •The balance of risks and benefits in depressive disor- remission of symptoms then withdrawn slowly over at ders in under 18 year olds is favourable for fluoxetine least 6-12 weeks.24 •There is no clear evidence of an increased risk of self-harm or suicidal thoughts in young adults older Increased suicidal behavioural and self-harm with SSRIs than 18 years. However, as individuals mature at dif- In December 2004, the Medicines and Healthcare ferent rates, young adults should be closely monitored products Regulatory Authority (MHRA) issued a final •As the number of prescriptions for SSRIs has been report from the expert working group on the safety increasing, there has been no increase in the popula- of the SSRIs.25 tion suicide rate, although a range of factors may Their conclusions were: affect results. •There is an increased rate of self-harm and suicidal There has been much debate as to the effect of thoughts with some SSRIs compared with placebo in the MHRA and other national authorities’ restric- children and adolescents tions on the use of SSRIs and other antidepressants •The balance of risks and benefits in depressive dis- in those under 18 years old. In the UK there is no evi-

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dence of a recent change in the suicide rate in chil- dren and adolescents.26 Conversely, data from the USA and the Netherlands indicate an increase in the suicide rate for children and adolescents following the restrictions.27

Antidepressants during pregnancy and breastfeeding Pregnancy Treating depression in pregnancy requires a multi- disciplinary approach to consider extensively the indi- vidual circumstances and healthcare of both the mother and baby. There are considerable risks in not adequately treating depression in pregnancy and high relapse rates in those who stop antidepressants dur- ing pregnancy.16 Psychotherapy such as brief CBT and self-help strategies should be considered in mild depression, and for those with moderate or severe depression, psychotherapy may be combined with an antidepressant. TCAs such as amitriptyline, imipramine and nortriptyline have been widely used in pregnancy and are often considered the agents of choice.28 If they are poorly tolerated or inappropriate then fluoxetine or sertraline are often considered.16,28 SSRIs (especially paroxetine and fluoxetine) have been associated with foetal heart defects in the first trimester but the absolute risk remains small.29 Exposure to an SSRI after 20 weeks of pregnancy may also increase the risk of persistent pulmonary hyper- tension in the newborn and all neonates exposed to antidepressants in the third trimester may suffer dis- continuation symptoms such as irritability, agitation or seizures.16 Other newer generation antidepressants have few supporting data so cannot currently be rec- ommended. The evidence base in pregnancy is always growing and changing, therefore obtaining the most up to date information at the time of treating the indi- vidual is essential.

Breastfeeding Choosing an antidepressant in a nursing mother is another complex decision, which should involve an individual assessment of the risks and benefits to the mother and infant. Consideration should also be given to the antidepressant the infant is exposed to during pregnancy and the risks associated with stop- ping or continuing the drug. In general imipramine, nortriptyline and sertraline are tacitly preferred, as drug levels in breast milk are low or undetectable.16,28

Future developments There are disappointingly few antidepressants in development and only two predicted to launch in

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2014 (see Table 3). Future research is likely to focus and depression severity. JAMA 2010;303:47-53. on either strategies to augment antidepressants, the 9. Kirsch I, Deacon B, Huedo-Medina T, et al. Initial Severity and anti- depressant benefits: A meta-analysis of data submitted to the food and effects of combining antidepressants or extending the drug administration. PLOS Med 2008;5(2):e45. www.plosmedicine.org indications for current antidepressants. Future devel- 10. Papakostas G, Perlis R, Scalia M, et al. A meta-analysis of early sus- opment of antidepressants needs to consider new tained response rates between antidepressants and placebo for the treat- ment of major depressive disorder. J Clin Psychopharm 2006;26:56-60. models for animal testing and extend beyond the 11. Geddes J, Carner S, Davies C, et al. Relapse prevention with antide- monoamine system.30,31 pressant drug treatment in depressive disorders: a systematic review. Lancet 2003;361:653-61. 12. Cipriani A, Furukawra T, Salanti G, et al. Comparative efficacy and Summary acceptability of 12 new-generation antidepressants: a multiple-treat- Effective treatment and management of depression ments meta-analysis. Lancet 2009;373:746-58. is a challenge for all healthcare professionals. 13. Artigas F, Nutt D, Shelton R. Mechanism of action of antidepres- sants. Psychopharm Bull 2002;36:(suppl. 2):123-31. Antidepressants remain an appropriate treatment for 14. Stahl S. Novel mechanism of antidepressant action: moderate and severe depression, or for mild depres- and dopamine disinhibition plus melatonergic agonism. Int J Neuropsychopharm 2007;10:575-8. sion or subtherapeutic depression that has persisted. 15. Schatzberg A, Blier P, Delgada P, et al. Antidepressant Discontinuation The SSRIs are recommended first-line because of syndrome: Consensus panel recommendations for clinical management their superior safety profile and better tolerability. and additional research. J Clin Psychiatry 2006;67(suppl. 4):27-30. 16. Taylor D, Carol P, Kapur S. The Maudsley Prescribing Guidelines, Further antidepressant choices depend in part on 11th Edition. Chichester: Wiley-Blackwell, 2012. adverse reaction profile, interaction potential, the 17. Nierenberg M, Fava M, Trivedi M, et al. A comparison of lithium evidence base, pharmacological properties and and T3 augmentation following two failed medication treatments for depression: A STAR*D Report. Am J Psychiatry 2006;163:1519-30. patient preference. In treatment-resistant cases, a 18. Rojo JE, Ros S, Aguera L, et al. Combined antidepressants: clinical variety of augmentation and combination strategies experience. Acta Psychiatrica Scand 2005;112:25-31. have been tried with some success. Problems that can 19. McGrath P, Stewart J, Fava M, et al. Tranylcypromine versus ven- lafaxine plus mirtazapine following three failed antidepressant med- occur with antidepressant treatment include an ication trials for depression: A STAR*D Report. Am J Psychiatry increased risk of bleeding, hyponatraemia, serotonin 2006;163:1531-41. syndrome and discontinuation symptoms, all of 20. Abajo F, Garcia-Rodriguez L. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and which should be closely monitored for. venlafaxine therapy. Arch Gen Psychiatry 2008;65:795-803. 21. Bleakley S, Moghul S, Yeo S, Baldwin D. Suspected serotonin syn- Declaration of interests drome following treatment with fentanyl and venlafaxine. Progress in Neurology and Psychiatry 2011;15:36. Stephen Bleakley has worked on advisory panels for 22. Boyer EW, Shannon M. Current concepts. The serotonin syndrome. Sunovion and Roche and attended educational New Engl J Med 2005;352:1112-20. events sponsored by Lilly and Lundbeck. 23. Taylor D, Stewart S, Connolly A. Antidepressant withdrawal symp- toms - telephone calls to a national medication helpline. J Affect Disord 2006;95:129-33. Stephen Bleakley, Deputy Chief Pharmacist, Southern 24. National Institute for Health and Care Excellence. Depression in Health NHS Foundation Trust; Director: The College of children and young people. Clinical Guideline CG28. NICE, 2005. http://guidance.nice.org.uk/CG28 Mental Health Pharmacy 25. Medicines and Healthcare Products Regulatory Agency. SSRI antide- pressants - Findings of the Committee on Safety of Medicines. MHRA, References 2004. www.mhra.gov.uk 26. Wheeler BW, Gunnell D, Metcalfe C, et al. The population impact 1. World Health Organization. Mental Health. Depression. on incidence of suicide and non-fatal self harm of regulatory action http://www.who.int/en/ against the use of selective serotonin reuptake inhibitors in under 2. Keller MB, Lavori PW, Rice J, et al. The persistent risk of chronicity in 18s in the United Kingdom: ecological study. BMJ 2008;336(7643): recurrent episodes of nonbipolar major depressive disorder: a prospec- 542-5. tive follow-up. Am J Psychiatry 1986;143:24-8. 27. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects 3. Mueller T, Leon A, Keller M, et al. Recurrence after recovery from of regulators’ suicidality warnings on SSRI prescriptions and suicide in major depressive disorder during 15 years of observational follow up. children and adolescents. Am J Psychiatry 2007;164:1356-63. Am J Psychiatry 1999;156:1000-6. 28. National Institute for Health and Care Excellence. Antenatal and 4. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guide- postnatal mental health. Clinical Guideline CG45. NICE, 2007. lines for treating depressive disorders with antidepressants: A revision http://guidance.nice.org.uk/CG45 of the 2000 British Association for Psychopharmacology guidelines. J 29. MHRA. Fluoxetine: possible small risk of congenital cardiac defects. Psychopharm 2008;22:343-96. Drug Safety Update 2010;3(8):4. 5. National Institute for Health and Care Excellence. Depression in 30. Hendrie C, Stanford C, Robinson E, et al. The failure of the antide- adults. Clinical Guideline CG90. NICE, 2009. http://guidance. pressant drug discovery process is systemic. J Psychpharmacol nice.org.uk/CG90 2013;27:407-16. 6. Posternak MA, Miller I. Untreated short-term course of major depres- 31. Greener M. Beyond serotonin: new approaches to the management sion: a meta-analysis of outcomes from studies using wait-list control of depression. Progress in Neurology and Psychiatry 2013;17:23-5. groups. J Affect Disord 2001;66:139-46. 32. Bazire S. Psychotropic Drug Directory. Malta: Lloyd-Reinhold 7. Walsh T, Seidman S, Sysko R, et al. Placebo response in studies of major Communications LLP, 2012. depression variable, substantial and growing. JAMA 2001;287:1840-7. 33. Baxter K. Stockley’s Drug Interactions, 9th edn. London: 8. Fournier J, DeRubeis R, Hollon S, et al. antidepressant drug effects Pharmaceutical Press, 2010.

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